Molecular Mechanisms in Allergy and Clinical Immunology
Cyclic nucleotide phosphodiesterases,☆☆

https://doi.org/10.1067/mai.2001.119555Get rights and content

Abstract

Cyclic nucleotide second messengers (cAMP and cGMP) play a central role in signal transduction and regulation of physiologic responses. Their intracellular levels are controlled by the complex superfamily of cyclic nucleotide phosphodiesterase (PDE) enzymes. Continuing advances in our understanding of the molecular pharmacology of these enzymes has led to the development of selective inhibitors as therapeutic agents for disease states ranging from cancer and heart failure to depression and sexual dysfunction. Several PDE types have been identified as therapeutic targets for immune/inflammatory diseases. This article briefly reviews the available in vitro, preclinical, and clinical data supporting the potential for selective PDE inhibitors as immunomodulatory agents. (J Allergy Clin Immunol 2001;108:671-80.)

Section snippets

Classification and structural biology

Table I shows the current classification scheme for cyclic nucleotide PDEs. Eleven distinct families (or types) are differentiated functionally on the basis of substrate specificity and sensitivity to endogenous/exogenous regulators and genetically on the basis of sequence homology (3 additional families have been reported, but the data available at this time are insufficient for their inclusion in Table I).13, 14, 15, 16, 17 Most of the families include more than 1 gene product (subtype,

Pharmacology

The general schema for the formation and degradation of cyclic nucleotides is depicted in Fig 1.

. Cyclic nucleotide signaling and homeostasis. Activation of ACs (1) results in the generation of cAMP from adenosine triphosphate (ATP; 2) . Four molecules of cAMP cooperatively bind to the 2 regulatory subunits of inactive cAK (3) , resulting in disengagement of 2 active catalytic subunits that are capable of protein phosphorylation (4) . The hydrolysis of cAMP to inactive 5′-adenosine monophosphate

In vitro effects

Inflammatory cells are exquisitely sensitive to alterations in cyclic nucleotide levels; interestingly, modulation of immune cell function by selective PDE inhibitors is limited to specific PDE types, probably as a result of compartmentalization of cyclic nucleotide and PDE pools. In immune cells, elevation of intracellular cAMP, mediated predominantly through inhibition of PDE4, results in a wide range of anti-inflammatory effects, as summarized in Table II.

. cAMP-PDE expression and

In vivo effects

PDE inhibitors have been evaluated as potential antidepressants, anti-inflammatory agents, antiproliferative agents, antihypertensive and cardiovascular agents, and cytoprotective agents.13, 116, 117, 118, 119, 120 To date, clinical development of selective PDE inhibitors has focused primarily on PDE3, PDE4, and PDE5. Despite early promise, clinical development of PDE3 inhibitors for congestive heart failure was essentially abandoned because of a concomitant increase in the incidence of cardiac

Conclusions

The past several years have witnessed significant advances in our understanding of the molecular pharmacology of cyclic nucleotide PDEs. With the advent of second-generation PDE4 inhibitors, the continued success of PDE5 inhibitors, and recent advances in rational structure/function drug design, the therapeutic promise of selective PDE inhibitors may soon be realized.

Acknowledgements

I would like to thank Drs Susan Jerian, Richard McFarland, and Mercedes Sirabian for their review of the manuscript. I would also like to thank Ms Jacqueline Schaffer for her concept and rendering of Fig 1.

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    The opinions expressed are those of the author and are not necessarily those of the US Food and Drug Administration.

    ☆☆

    Reprint requests: David M. Essayan, MD, DCTDA, OTRR, CBER, USFDA, 1401 Rockville Pike, HFM-579, Rockville, MD 20852.

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